PROJECT SUMMARY/ABSTRACT Signal transduction occurs when an extracellular signaling molecule activates a specific receptor located on the cell surface or inside the cell. In turn, this receptor triggers a biochemical chain of events inside the cell, creating a response. The signaling network mediated by insulin-like growth factor 1 (IGF-1) receptor is fundamentally important for the regulation of a number of cellular functions, including the neuroprotection of post-mitotic cells. The specific objectives of this application are to investigate the mechanism of IGF-1R- mediated signaling in both rod and cone photoreceptors, and the regulation of the cellular processes required to promote and sustain photoreceptor functionality and viability. The research strategy outlined in this proposal is built upon the recently uncovered function of IGF-1R in photoreceptor neuroprotection, and a fundamental property of IGF-1R in many other cell tissues. The study proposed herein will define how IGF-1R regulates photoreceptor functions. Using genetically modified mice and pharmacological agents, we have identified changes in cellular signaling and gene expression in the retina. We have identified several activators and negative regulators of IGF-1R signaling in the retina, and have developed methods for manipulating IGF-1R activation to detect the impact on photoreceptor functions. We will use these methods to determine how IGF-1R signaling regulates photoreceptor neuroprotection and other cellular functions. We will study the source of IGF-1 to activate IGF-1R and the consequence of its absence in rods (Aim 1). We will test the mechanisms of IGF-1R activation and deactivation in the retina (Aim 2). Successful completion of our studies could benefit millions of people who are blind from rod and cone cell loss. Our new and innovative approaches will facilitate future translational application of our work, with the goal of applying our findings to the treatment of human retinal degenerations. Elucidating these mechanisms is critical to advancing our understanding of basic photoreceptor cell biology and pathobiological mechanisms underlying the photoreceptor degeneration that is frequently associated with defects in anabolic processes.